Since ancient times, glaucoma has been known as an incurable disease. Glaucoma is a disease of the eye marked by increased pressure within the eyeball, damage to the optic disc, and gradual loss of vision. Normally, aqueous humor, which supplies nutrients to the lens and cornea and maintains normal intraocular pressure, is produced in the ciliary process. The aqueous humor circulates from the posterior chamber through the pupil and into the anterior chamber. It then drains through and is filtered by the trabecular meshwork, then through Schlemm's Canal and from there through the aqueous veins into the venous system. Elevated intraocular pressure most often results from increased resistance to the normal outflow of aqueous humor from the eye, however, on rare occasions, it is caused by hypersecretion of aqueous humor.
Open angle glaucoma, the most common form of glaucoma increases in frequency and severity with age. Many studies have been done to define the cause of glaucoma. According to these studies, resistance to the aqueous outflow increases and rate of aqueous production decreases with age. It has been suspected for many years that age related changes in trabecular meshwork are responsible for obstruction of aqueous humor outflow. It has been shown that a continuous decrease in trabecular meshwork cellularity occurs throughout life. When cells are lost, remaining cells may stretch, rather than divide to fill gaps. Eventually the trabecular meshwork cell population could become too small to cover the trabeculae. Trabecular meshwork cells are also located around and support the Canal. Loss of cells in the endothelium of Schlemm's canal may be important because resistance in the canal could be reduced initiating a cycle of increased flow and further breakdown. It has been suggested that increase resistance to aqueous outflow may result from compression of the Schlemm's canal, which has been shown experimentally to partially collapse at elevated intraocular pressure. Loss of trabecular meshwork cells would reduce their flow producing action, allow material to deposit in the canal, and contribute to collapse of the canal.
Age related changes in the trabecular extracellular matrix cause increases and accumulations in fibronectin and other extracellular glycoprotein in the drainage pathway of human eyes that may contribute to increased outflow resistance.
Current medication for glaucoma treatment seeks to reduce inflow or increase outflow of the aqueous humor without directing activities of trabecular meshwork cells. Such agents as beta blockers and other anti-hypertensive agents which reduce the amount of aqueous humor and control pressure in the eye.
When such medication no longer controls pressure, filtration surgery in preformed, to relieve the pressure. The trabeculectomy is the most popular technique. In this technique a passageway is made between the subconjunctival space and the anterior chamber by excising the sclera and episclera and then removing the trabeculae. The aqueous humor then passes through the trabeculectomy and goes under the conjunctiva to form a bleb. The success rate of standard filtration surgery ranges between 25-60% in aphakia patients (those without lenses) to 75-95% in phakic eyes. Problems with filtration surgery include scar formation that stops drainage and rarely blockage of trabeculectomy section by other structures in the eye. One means of controlling scarring is the application of 5-Fluorouracil [RN 51-21-8].
For prevention of scarring in the bleb after glaucoma surgery, 5-FU at amounts greater than 100 mg are used. This antimetabolic drug is used daily for a week as a subconjunctival injection of 5-15 mg to eliminate mitosis and migration of conjunctiva and Tenon's capsule fibroblast (mesodermal cells giving rise to connective tissue) toward the filtered bleb. A total dose of 105 mg of 5-FU is employed in treatment of the majority of patients. The threshold concentration for 5-FU toxicity to the cornea in the endothelium lies between 1 and 10 mg/ml for a 4 hour exposure. It is known that 5-FU inhibits fibroblasts.
Uracil is a pyrimidine base occurring in RNA. In some RNAs, especially low molecular weight amino acid transfer RNA of the cytoplasm, hypoxanthine and various methylated bases replace some of the native component. Certain bases (and their nucleosides and nucleotides) not usually occurring in nature act as chemotherapeutic and mutagenic agents, because they are readily incorporated into nucleic acids instead of the native bases. Among them are the uracil analogs 2-thio- and 5-Fluorouracil, 5-Bromouracil, and the guanine analogs 8-azaguanine and 2,6-diamanopurine. As a result of incorporation into the RNA, modified proteins are formed. This alteration becomes manifest soon after introduction of the analog and is relieved after its removal and replacement by the native base.
The alterations produced in this way vary even for any one organism. For the inducible beta galactosidease, they lead to a loss of activity; for the repressible alkaline phosphatase, the protein is still active but exhibits a different heat stability; and for one group of phage mutants in a restricted host, it may actually lead to the formation of a functional, rather than an inactive protein. Thus the action of the 5-Fluorouracil is unpredictable. Under certain unusual circumstances, the result of treatment with 5-Fluorouracil results in an altered protein which may sufficiently resemble that of the native type and be produced in sufficient amounts so as to permit function and/or growth.
5-FU is a cytostatic drug with antimetabolitic action which inhibits thymidine synthetase and thus formation of DNA. Present uses of 5-Fluorouracil include anticancer agents and as an antiscarring agent after glaucoma filtration surgery.
Uncontrolled stimulation of mitosis creates cancer. Thus, anticancer drugs are generally antimitotic. It is clear from present literature, that 5-FU, being anticytotic was considered to be inhibitory to cell growth. The anticytotic action of 5-FU appear at higher doses occurs for both mitotic and migratory processes. For treatment of cancer, the 5-FU may be administered orally, by injection, through implants, creams, ointments and drops, depending on the location and type of cancer. Dosages range from 300 to 1000 mg/m2.
Methods of applying 5-Fluorouracil include injections, creams, drops, and implants are described in U.S. Pat. Nos. 4,863,457 and 4,997,652, incorporated herein by reference. To achieve antiscarring activity 5-Fluorouracil is given in dosages far exceeding the 10 ug/ml used in the present invention. Jon Ruderman et al discuss the use of Fluorouracil in "A Prospective, Randomized Study of 5-Fluorouracil and Filtration surgery", Tr. Am. Ophth. Soc. vol. LXXXV, 1987 and "Low-Dose 5-Fluorouracil and Glaucoma Filtration Surgery", Ophthalmic Surgery, vol. 20, No. 5. These studies showed even at low dosages, 5-Fluorouracil provided significantly lower postoperative intraocular pressure.
The inventor is unaware of any suggestion that 5-Fluorouracil can be effective treatment for glaucoma without filtration surgery.